PROJECT SUMMARY Up to 40% of patients who undergo mastectomy suffer from chronic pain, defined as pain lasting greater than 3 months. Nevertheless, mastectomy remains a mainstay of treatment for over 25% of breast cancer patients, necessitating novel, definitive solutions for chronic pain. Previous studies have documented that breast cancer patients with post-surgical pain experience worse quality-of-life with respect to physical and psychological well- being. Over 10% of opioid nave patients who undergo breast cancer surgery require opioids for pain relief at least three months after surgery. Current pharmacologic strategies including non-steroidal anti-inflammatory drugs (NSAIDs) and neuropathic drugs (e.g. gabapentin or amitriptyline) are often insufficient due to adverse effects, incomplete pain relief, and poor patient compliance. Several reports have demonstrated that cutaneous nerve injury substantially contributes to post-mastectomy pain. Altered sensation, including `pins and needles' sensation and/or shock-like, burning, or stabbing pain in the known distribution of chest wall sensory nerves suggest a neuropathic etiology. A strategy which addresses the underlying nerve injury would offer an opportunity to definitively treat chronic post-mastectomy pain. The regenerative peripheral nerve interface (RPNI) has emerged as a novel strategy to treat neuromas in peripheral nerves. The RPNI consists of the residual peripheral nerve end implanted in a muscle graft, following surgical resection of the injured terminal nerve portion (neuroma). The muscle graft is separated from its native nerve input, leaving neuromuscular junctions open for ingrowth of nerve fibers from the implanted nerve; animal studies show that this provides a physiologic end-organ for the implanted nerve without neuroma recurrence. We have performed RPNIs to treat painful neuromas associated with limb amputation, with significant reductions in patient-reported pain. Recently, we have performed RPNIs to treat intercostal neuromas in patients with chronic post-mastectomy pain. Limited follow-up suggests that these patients experience substantial improvement in their pain, although formal evaluation is required. Our central hypothesis is that intercostal nerve RPNI surgery significantly reduces chronic post-mastectomy pain without neuroma recurrence. We will employ a cross-over study design assess the efficacy of RPNI surgery for intercostal neuroma while optimizing patient enrollment. Aim 1: To demonstrate the efficacy of RPNI surgery to reduce post-mastectomy pain and opioid consumption. We will obtain patient-reported outcomes (PRO's), using previously validated tools, to measure the effect of RPNI surgery on post-mastectomy pain and opioid use in this pilot clinical study. Aim 2: To demonstrate absence of neuroma recurrence in post-mastectomy patients after intercostal RPNI surgery. Neuroma recurrence in patients treated with intercostal RPNI will be evaluated using physical exam findings and ultrasound imaging.